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  • 1.
    Banihani, Rudaina
    et al.
    Univ Toronto, Dept Paediat, Div Dev Paediat, Toronto, ON M5S 1A1, Canada.;Holland Bloorview Kids Rehabil Hosp, Child Dev Program, Toronto, ON, Canada..
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Halliday, William
    Univ Toronto, Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON M5G 1X8, Canada..
    Kobayashi, Jeff
    Univ Toronto, Hosp Sick Children, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada..
    Kawamura, Anne
    Univ Toronto, Dept Paediat, Div Dev Paediat, Toronto, ON M5S 1A1, Canada.;Holland Bloorview Kids Rehabil Hosp, Child Dev Program, Toronto, ON, Canada..
    McAdam, Laura
    Univ Toronto, Dept Paediat, Div Dev Paediat, Toronto, ON M5S 1A1, Canada.;Holland Bloorview Kids Rehabil Hosp, Child Dev Program, Toronto, ON, Canada..
    Ray, Peter N.
    Univ Toronto, Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Yoon, Grace
    Univ Toronto, Hosp Sick Children, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada..
    A Novel Mutation in DMD (c.10797+5G > A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability2016In: Journal of Developmental and Behavioral Pediatrics, ISSN 0196-206X, E-ISSN 1536-7312, Vol. 37, no 3, p. 239-244Article in journal (Refereed)
    Abstract [en]

    Background: Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy. Patient: The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD. Conclusion: Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.

  • 2.
    Baskin, Berivan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Choufani, Sanaa
    Chen, Yi-an
    Shuman, Cheryl
    Parkinson, Nicole
    Lemyre, Emmanuelle
    Stavropoulos, Dimitri J
    Ray, Peter N
    Weksberg, Rosanna
    High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome2014In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 133, no 3, p. 321-330Article in journal (Refereed)
    Abstract [en]

    Beckwith-Wiedemann syndrome (BWS), an overgrowth and tumor predisposition syndrome is clinically heterogeneous. Its variable presentation makes molecular diagnosis particularly important for appropriate counseling of patients with respect to embyronal tumor risk and recurrence risk. BWS is characterized by macrosomia, omphalocele, and macroglossia. Additional clinical features can include hemihyperplasia, embryonal tumors, umbilical hernia, and ear anomalies. BWS is etiologically heterogeneous arising from dysregulation of one or both of the chromosome 11p15.5 imprinting centers (IC) and/or imprinted growth regulatory genes on chromosome 11p15.5. Most BWS cases are sporadic and result from loss of maternal methylation at imprinting center 2 (IC2), gain of maternal methylation at imprinting center 1 (IC1) or paternal uniparental disomy (UPD). Heritable forms of BWS (15%) have been attributed mainly to mutations in the growth suppressor gene CDKN1C, but have also infrequently been identified in patients with copy number variations (CNVs) in the chromosome 11p15.5 region. Four hundred and thirty-four unrelated BWS patients referred to the molecular diagnostic laboratory were tested by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Molecular alterations were detected in 167 patients, where 103 (62%) showed loss of methylation at IC2, 23 (14%) had gain of methylation at IC1, and 41 (25%) showed changes at both ICs usually associated with paternal UPD. In each of the three groups, we identified patients in whom the abnormalities in the chromosome 11p15.5 region were due to CNVs. Surprisingly, 14 patients (9%) demonstrated either deletions or duplications of the BWS critical region that were confirmed using comparative genomic hybridization (CGH) array analysis. The majority of these CNVs were associated with a methylation change at IC1. Our results suggest that CNVs in the 11p15.5 region contribute significantly to the etiology of BWS. We highlight the importance of performing deletion/duplication testing in addition to methylation analysis in the molecular investigation of BWS in order to improve our understanding of the molecular basis of this disorder, and to provide accurate genetic counselling.

  • 3.
    Baskin, Berivan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Hosp Sick Children, Dept Pediat Lab Med, Toronto, Canada.
    Kalia, Lorraine V.
    Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, Canada; Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, Canada; Univ Toronto, Univ Hlth Network, Div Neurol, Dept Med, Toronto, Canada.
    Banwell, Brenda L.
    Univ Philadelphia, Perelman Sch Med, Childrens Hosp Philadelphia, Philadelphia, USA.
    Ray, Peter N.
    Hosp Sick Children, Dept Pediat Lab Med, Toronto, Canada; Univ Toronto, Dept Mol Genet, Toronto, Canada.
    Yoon, Grace
    Univ Toronto, Hosp Sick Children, Dept Pediat, Div Clin & Metab Genet, Toronto, Canada; Univ Toronto, Hosp Sick Children, Dept Pediat, Div Neurol, Toronto, Canada.
    Complex genomic rearrangement in SPG11 due to a DNA replication-based mechanism2017In: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, p. 1792-1794Article in journal (Refereed)
  • 4.
    Baskin, Berivan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Skinner, Jon R
    Sanatani, Shubhayan
    Terespolsky, Deborah
    Krahn, Andrew D
    Ray, Peter N
    Scherer, Stephen W
    Hamilton, Robert M
    TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations2013In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 132, no 11, p. 1245-1252Article in journal (Refereed)
    Abstract [en]

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of right ventricular free wall myocardium and life-threatening ventricular arrhythmias. A missense mutation, c.1073C>T (p.S358L) in the transmembrane protein 43 (TMEM43) gene, has been genetically identified to cause ARVC type 5 in a founder population from Newfoundland. It is unclear whether this mutation occurs in other populations outside of this founder population or if other variants of TMEM43 are associated with ARVC disease. We sought to identify non-Newfoundland individuals with TMEM43 variants among patient samples sent for genetic assessment for possible ARVC. Of 195 unrelated individuals with suspected ARVC, mutation of desmosomal proteins was seen in 28 and the p.S358L TMEM43 mutation in six. We identified a de novo p.S358L mutation in a non-Newfoundland patient and five separate rare TMEM43 (four novel) sequence variants in non-Newfoundland patients, each occurring in an evolutionarily conserved amino acid. TMEM43 mutations occur outside of the founder population of the island of Newfoundland where it was originally described. TMEM43 sequencing should be incorporated into clinical genetic testing for ARVC patients.

  • 5.
    Baskin, Berivan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Stavropoulos, Dimitri J.
    Rebeiro, Paige A.
    Orr, Jennifer
    Li, Martin
    Steele, Leslie
    Marshall, Christian R.
    Lemire, Edmond G.
    Boycott, Kym M.
    Gibson, William
    Ray, Peter N.
    Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms2014In: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, Vol. 2, no 6, p. 539-547Article in journal (Refereed)
    Abstract [en]

    Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2–5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45–49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.

  • 6. Lines, Matthew A
    et al.
    Rupar, C Anthony
    Rip, Jack W
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Ray, Peter N
    Hegele, Robert A
    Grynspan, David
    Michaud, Jean
    Geraghty, Michael T
    Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation2014In: JIMD Reports: Volume 12 / [ed] Johannes Zschocke, K Michael Gibson, Garry Brown, Eva Morava & Verena Peters, Springer, 2014, Vol. 12, p. 79-84Chapter in book (Refereed)
    Abstract [en]

    Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434:c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.

  • 7. Mangerel, Joshua
    et al.
    Price, Aryeh
    Castelo-Branco, Pedro
    Brzezinski, Jack
    Buczkowicz, Pawel
    Rakopoulos, Patricia
    Merino, Diana
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wasserman, Jonathan
    Mistry, Matthew
    Barszczyk, Mark
    Picard, Daniel
    Mack, Stephen
    Remke, Marc
    Starkman, Hava
    Elizabeth, Cynthia
    Zhang, Cindy
    Alon, Noa
    Lees, Jodi
    Andrulis, Irene L.
    Wunder, Jay S.
    Jabado, Nada
    Johnston, Donna L.
    Rutka, James T.
    Dirks, Peter B.
    Bouffet, Eric
    Taylor, Michael D.
    Huang, Annie
    Malkin, David
    Hawkins, Cynthia
    Tabori, Uri
    Alternative lengthening of telomerases is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 128, no 6, p. 853-862Article in journal (Refereed)
    Abstract [en]

    Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.

  • 8. Molinski, Steven V
    et al.
    Gonska, Tanja
    Huan, Ling Jun
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Janahi, Ibrahim A
    Ray, Peter N
    Bear, Christine E
    Genetic, cell biological, and clinical interrogation of the CFTR mutation c.3700 A>G (p.Ile1234Val) informs strategies for future medical intervention2014In: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 16, no 8, p. 625-632Article in journal (Refereed)
    Abstract [en]

    Purpose:

    The purpose of this study was to determine the molecular consequences of the variant c.3700 A>G in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a variant that has been predicted to cause a missense mutation in the CFTR protein (p.Ile1234Val).

    Methods:

    Clinical assays of CFTR function were performed, and genomic DNA from patients homozygous for c.3700 A>G and their family members was sequenced. Total RNA was extracted from epithelial cells of the patients, transcribed into complementary DNA, and sequenced. CFTR complementary DNA clones containing the missense mutation p.Ile1234Val or a truncated exon 19 (p.Ile1234_Arg1239del) were constructed and heterologously expressed to test CFTR protein synthesis and processing.

    Results

    In vivo functional measurements revealed that the individuals homozygous for the variant c.3700 A>G exhibited defective CFTR function. We show that this mutation in exon 19 activates a cryptic donor splice site 18 bp upstream of the original donor splice site, resulting in deletion of six amino acids (r.3700_3717del; p.Ile1234_Arg1239del). This deletion, similar to p.Phe508del, causes a primary defect in folding and processing. Importantly, Lumacaftor (VX-809), currently in clinical trial for cystic fibrosis patients with the major cystic fibrosis-causing mutation, p.Phe508del, partially ameliorated the processing defect caused by p.Ile1234_Arg1239del.

    Conclusion:

    These studies highlight the need to verify molecular and clinical consequences of CFTR variants to define possible therapeutic strategies

  • 9. Torchia, Jonathon
    et al.
    Picard, Daniel
    Lafay-Cousin, Lucie
    Hawkins, Cynthia E.
    Kim, Seung-Ki
    Letourneau, Louis
    Ra, Young-Shin
    Ho, King Ching
    Chan, Tiffany Sin Yu
    Sin-Chan, Patrick
    Dunham, Christopher P.
    Yip, Stephen
    Ng, Ho-Keung
    Lu, Jian-Qiang
    Albrecht, Steffen
    Pimentel, Jose
    Chan, Jennifer A.
    Somers, Gino R.
    Zielenska, Maria
    Faria, Claudia C.
    Roque, Lucia
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Birks, Diane
    Foreman, Nick
    Strother, Douglas
    Klekner, Almos
    Garami, Miklos
    Hauser, Peter
    Hortobagyi, Tibor
    Bognar, Laszlo
    Wilson, Beverly
    Hukin, Juliette
    Carret, Anne-Sophie
    Van Meter, Timothy E.
    Nakamura, Hideo
    Toledano, Helen
    Fried, Iris
    Fults, Daniel
    Wataya, Takafumi
    Fryer, Chris
    Eisenstat, David D.
    Scheineman, Katrin
    Johnston, Donna
    Michaud, Jean
    Zelcer, Shayna
    Hammond, Robert
    Ramsay, David A.
    Fleming, Adam J.
    Lulla, Rishi R.
    Fangusaro, Jason R.
    Sirachainan, Nongnuch
    Larbcharoensub, Noppadol
    Hongeng, Suradej
    Barakzai, Muhammad Abrar
    Montpetit, Alexandre
    Stephens, Derek
    Grundy, Richard G.
    Schueller, Ulrich
    Nicolaides, Theodore
    Tihan, Tarik
    Phillips, Joanna
    Taylor, Michael D.
    Rutka, James T.
    Dirks, Peter
    Bader, Gary D.
    Warmuth-Metz, Monika
    Rutkowski, Stefan
    Pietsch, Torsten
    Judkins, Alexander R.
    Jabado, Nada
    Bouffet, Eric
    Huang, Annie
    Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis2015In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 16, no 5, p. 569-582Article in journal (Refereed)
    Abstract [en]

    Background Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0.004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2.02 (95% CI 1.04-3.85; p=0.038) and 3.98 (1.71-9.26; p=0.001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. Interpretation An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.

  • 10. Yoon, G.
    et al.
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Tarnopolsky, M.
    Boycott, K. M.
    Geraghty, M. T.
    Sell, E.
    Goobie, S.
    Meschino, W.
    Banwell, B.
    Ray, P. N.
    Autosomal recessive hereditary spastic paraplegia: clinical and genetic characteristics of a well-defined cohort2013In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 14, no 3-4, p. 181-188Article in journal (Refereed)
    Abstract [en]

    We describe the clinical and genetic features of a well-characterized cohort of patients with autosomal recessive hereditary spastic paraplegia (ARHSP) in the province of Ontario. Patients with documented corticospinal tract abnormalities were screened by whole gene sequencing and multiplex ligation probe amplification for mutations in nine genes known to cause ARHSP. Of a cohort of 39 patients, a genetic diagnosis was established in 17 (44 %) and heterozygous mutations were detected in 8 (21 %). Mutations were most frequent in SPG7 (12 patients), followed by SPG11 (10 patients), PNPLA6 (SPG39, 2 patients), and ZFYVE26 (SPG15, 2 patients). Although there are associations between some clinical manifestations of ARHSP and specific genes, many patients are tested at an early stage of the disease when phenotype/genotype correlations are not obvious. Accurate molecular characterization of well-phenotyped cohorts of patients will be essential to establishing the natural history of these rare degenerative disorders to enable future clinical trials.

  • 11. Zhukova, Nataliya
    et al.
    Ramaswamy, Vijay
    Remke, Marc
    Martin, Dianna C
    Castelo-Branco, Pedro
    Zhang, Cindy H
    Fraser, Michael
    Tse, Ken
    Poon, Raymond
    Shih, David J H
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ray, Peter N
    Bouffet, Eric
    Dirks, Peter
    von Bueren, Andre O
    Pfaff, Elke
    Korshunov, Andrey
    Jones, David T W
    Northcott, Paul A
    Kool, Marcel
    Pugh, Trevor J
    Pomeroy, Scott L
    Cho, Yoon-Jae
    Pietsch, Torsten
    Gessi, Marco
    Rutkowski, Stefan
    Bognar, Laszlo
    Cho, Byung-Kyu
    Eberhart, Charles G
    Conter, Cecile Faure
    Fouladi, Maryam
    French, Pim J
    Grajkowska, Wieslawa A
    Gupta, Nalin
    Hauser, Peter
    Jabado, Nada
    Vasiljevic, Alexandre
    Jung, Shin
    Kim, Seung-Ki
    Klekner, Almos
    Kumabe, Toshihiro
    Lach, Boleslaw
    Leonard, Jeffrey R
    Liau, Linda M
    Massimi, Luca
    Pollack, Ian F
    Ra, Young Shin
    Rubin, Joshua B
    Van Meir, Erwin G
    Wang, Kyu-Chang
    Weiss, William A
    Zitterbart, Karel
    Bristow, Robert G
    Alman, Benjamin
    Hawkins, Cynthia E
    Malkin, David
    Clifford, Steven C
    Pfister, Stefan M
    Taylor, Michael D
    Tabori, Uri
    WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma2014In: Acta neuropathologica communications, ISSN 2051-5960, Vol. 2, article id 174Article in journal (Refereed)
    Abstract [en]

    TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of gammaH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

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